Acetaminophen and caffeine are analgesic or psychoactive drugs in human life that plays a major role in food and medicinal chemistry. Caffeine increases the efficacy of acetaminophen by improving its absorption, thereby prolonging analgesic action. Caffeine might exacerbate symptoms of anxiety if being prone to them. Taking these medications for a headache or migraine may cause problems for human life. Developing a sensitive, selective, easy, quick, and economical electroanalytical approach for the simultaneous detection of acetaminophen and caffeine has been a major area of research since they typically coexist in biological fluids and oxidize at overlapping potentials. Voltammetry has become one of the most commonly used and an important method amongst the other methods due to its high sensitivity and reliability. Moreover, carbon materials, metal/metal oxides/nanoparticles, and polymer-based materials have enhanced researchers' attention for the strategy and growth of electrochemical sensors for acetaminophen and caffeine. This compilation is a comprehensive effort to address the growing need for materials and their simultaneous detection of acetaminophen and caffeine. In this study, the validation parameters (electrode surface area, catalytic activity, electron transfer kinetics, potential window, sensitivity, and selectivity) were evaluated and provided a strong foundation for evaluating the effectiveness of materials and techniques. This review highlights the most widely used voltammetric methods for simultaneous electrochemical determination of acetaminophen and caffeine, and it explains the interference effect of acetaminophen and caffeine along with similar structural components. Finally, the topic has been concluded with existing challenges and prospects.